通过爱泼斯坦-巴尔病毒gp350实现补体受体结合和病毒中和的结构基础。

Structural basis for complement receptor engagement and virus neutralization through Epstein-Barr virus gp350.

作者信息

Joyce M Gordon, Bu Wei, Chen Wei-Hung, Gillespie Rebecca A, Andrews Sarah F, Wheatley Adam K, Tsybovsky Yaroslav, Jensen Jaime L, Stephens Tyler, Prabhakaran Madhu, Fisher Brian E, Narpala Sandeep R, Bagchi Meghna, McDermott Adrian B, Nabel Gary J, Kwong Peter D, Mascola John R, Cohen Jeffrey I, Kanekiyo Masaru

机构信息

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD 20817, USA; Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

出版信息

Immunity. 2025 Feb 11;58(2):295-308.e5. doi: 10.1016/j.immuni.2025.01.010. Epub 2025 Feb 4.

DOI:10.1016/j.immuni.2025.01.010

PMID:39909035

Abstract

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with malignancies in humans. Viral infection of B cells is initiated by the viral glycoprotein 350 (gp350) binding to complement receptor 2 (CR2). Despite decades of effort, no vaccines or curative agents have been developed, partly due to lack of atomic-level understanding of the virus-host interface. Here, we determined the 1.7 Å structure of gp350 in complex with CR2. CR2 binding of gp350 utilized the same set of Arg residues required for recognition of its natural ligand, complement C3d. We further determined the structures of gp350 in complex with three potently neutralizing antibodies (nAbs) obtained from vaccinated macaques and EBV-infected individuals. Like the CR2 interaction, these nAbs targeted the acidic pocket within the CR2-binding site on gp350 using Arg residues. Our results illustrate two axes of molecular mimicry-gp350 versus C3d and CR2 versus EBV nAbs-offering insights for EBV vaccines and therapeutics development.

摘要

爱泼斯坦-巴尔病毒（EBV）可引发传染性单核细胞增多症，并与人类恶性肿瘤相关。病毒糖蛋白350（gp350）与补体受体2（CR2）结合可启动B细胞的病毒感染。尽管经过数十年努力，但尚未开发出疫苗或治愈药物，部分原因是缺乏对病毒-宿主界面的原子水平理解。在此，我们确定了与CR2结合的gp350的1.7 Å结构。gp350与CR2的结合利用了识别其天然配体补体C3d所需的同一组精氨酸残基。我们还确定了gp350与从接种疫苗的猕猴和EBV感染个体中获得的三种强效中和抗体（nAb）结合的结构。与CR2相互作用一样，这些nAb利用精氨酸残基靶向gp350上CR2结合位点内的酸性口袋。我们的结果阐明了分子模拟的两个轴——gp350与C3d以及CR2与EBV nAb——为EBV疫苗和治疗药物的开发提供了见解。